Excision Repair Cross-complementation Group Research Articles

FTX promotes esophageal cancer progression and desensitizes esophageal cancer cells to ionizing radiation by microRNA-99a/b-3p/WEE1/ERCC1 axis

Abstract Objectives This study was conducted to uncover the underlying cellular and molecular mechanisms of FTX dysregulation in EC. Methods The gene expression in tumor tissues was detected using western blot, immunohistochemistry, and quantitative real-time polymerase chain reaction (qPCR). The dual-luciferase reporter and RNA FISH assays confirmed the interaction between miRNA and target genes. Mouse models for Xenograft and lung metastasis were used to assess EC cell tumorigenesis and metastasis. Results This study finds that up-regulated FTX in patients with esophageal cancer correlates with poor clinical outcomes. Silencing FTX inhibits esophageal cancer cell growth and migration in vitro and tumor metastasis in vivo. miR-99a/b-3p sensitizes esophageal cancer cells to ionizing radiation by WEE1 (Wee1-like protein kinase) and ERCC1 (excision repair cross-complementation group 1) in vitro. Conclusions FTX promotes the malignant biological phenotype of esophageal cancer cells. Mechanistically, FTX acts as a ceRNA to regulate the transcription of WEE1 and ERCC1 by sponging hsa-miR-99a/b-3p.

Perspectives in the investigation of Cockayne syndrome group B neurological disease: the utility of patient-derived brain organoid models.

Cockayne syndrome (CS) group B (CSB), which results from mutations in the excision repair cross-complementation group 6 (ERCC6) genes, which produce CSB protein, is an autosomal recessive disease characterized by multiple progressive disorders including growth failure, microcephaly, skin photosensitivity, and premature aging. Clinical data show that brain atrophy, demyelination, and calcification are the main neurological manifestations of CS, which progress with time. Neuronal loss and calcification occur in various brain areas, particularly the cerebellum and basal ganglia, resulting in dyskinesia, ataxia, and limb tremors in CSB patients. However, the understanding of neurodevelopmental defects in CS has been constrained by the lack of significant neurodevelopmental and functional abnormalities observed in CSB-deficient mice. In this review, we focus on elucidating the protein structure and distribution of CSB and delve into the impact of CSB mutations on the development and function of the nervous system. In addition, we provide an overview of research models that have been instrumental in exploring CS disorders, with a forward-looking perspective on the substantial contributions that brain organoids are poised to further advance this field.

Association of ERCC1 Gene Polymorphisms (rs3212986 and rs11615) With the Risk of Lung Cancer in a Population From Southeast Iran.

Polymorphisms within the excision repair cross-complementation group 1 (ERCC1), an essential component of DNA repair mechanisms, have been associated with various malignancies. This study aimed to evaluate the association of the single-nucleotide polymorphisms (SNPs) rs3212986 and rs11615 within the ERCC1 gene in non-small cell lung cancer (NSCLC) patients. Study Design: A case-control study. Genomic DNA was extracted from the peripheral blood samples of 83 NSCLC patients and 119 healthy individuals. The genetic diversity of SNPs rs3212986 and rs11615 was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The RFLP results were confirmed through sequencing. The TT genotype of the rs11615 SNP was associated with a higher risk of NSCLC development (odds ratio: 3.900, 95% confidence interval: 0.603, 22.866, P=0.050). Furthermore, the AA genotype of rs3212986 was related to a higher risk of NSCLC development (OR: 2.531, 95% CI: 1.017, 6.300, P=0.046). A significant association was observed between smoking and lung cancer (OR: 3.072, 95% CI: 1.715, 5.503, P<0.001). Moreover, among non-smokers, there was an association between lung cancer risk and the AA (OR: 6.825, 95% CI: 1.722, 27.044, P=0.006) and AC (OR: 2.503, 95% CI: 0.977, 6.412, P=0.056) genotypes of rs3212986. However, no correlation was found between the genotypes of these SNPs and patients' sensitivity to cisplatin and carboplatin (P ˃ 0.05). The rs11615-related TT genotype and the rs3212986-related AA genotype may be associated with a higher risk of lung cancer development.

Novel Candidate Single Nucleotide Polymorphisms of ERCC2 Gene that Influence Colorectal Cancer Susceptibility

Colorectal cancer (CRC) is the most common gastrointestinal malignancy and one of the top ten common cancers worldwide with approximately 2 million cases. There are multiple risk factors that could lead to CRC emergence; of which are genetic polymorphisms. Excision repair cross-complementing group 2 (ERCC2) gene encodes for ERCC2 enzyme which plays a crucial role in maintaining genomic integrity by removing DNA adducts. Several studies suggested that there could be a link between genetic polymorphisms of ERCC2 gene and the risk of CRC development. Hence the present study aims to validate the relationship between the following ERCC2 single nucleotide polymorphisms (rs13181, rs149943175, rs530662943, and rs1799790) and CRC susceptibility. A total of 121 participants were enrolled in this case control study; 72 CRC patients and 49 apparently healthy individuals. Genotyping was performed using polymerase chain reaction (PCR) followed by sequencing then the association between genetic polymorphisms and CRC susceptibility was examined. GA genotype and A allele of rs149943175 were associated with lower risk of CRC development. However, GA genotype and A allele carriers of rs530662943 had significantly increased risk compared to GG genotype. Additional stratified analyses showed that carriers of heterozygous genotype of rs149943175 who non-smokers, females or BMI figures less than 25 are less likely to develop CRC compared to wild genotype carriers. Taken together, genetic polymorphisms of ERCC2 modulate the susceptibility of CRC malignancy.

ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n= 343) and mutant (n= 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

The diagnostic value of inflammation-related genes in bronchopulmonary dysplasia

This study aims to explore the diagnostic value of inflammation-related genes in peripheral blood mononuclear cells in bronchopulmonary dysplasia (BPD). By using bioinformatics analysis, three datasets including GSE32472, GSE125873, and GSE220135, which contain whole-genome expression profile data of 251 neonates, were included. The GSE32472 dataset was used as a training dataset to detect differentially expressed genes between non-BPD and BPD neonates in peripheral blood mononuclear cells. The gene enrichment analysis (GSEA) was used to detect the pathway enrichment of up-regulated genes in BPD newborns. The main regulatory factors analysis (MRA) algorithm was used to filter the main regulatory genes in the inflammation-related pathway (GO:0006954). After obtaining the main regulatory genes, the expression of the main regulatory genes in the GSE32472, GSE125873, and GSE220135 datasets was detected. Through the logistic regression model, risk scoring was conducted for neonates, and the risk scores of non-BPD and BPD neonates were compared. Lastly, the classification performance of the model was evaluated using the area under the curve (AUC). The results showed that compared with non-BPD neonates, there were 486 up-regulated genes and 433 down-regulated genes in the peripheral blood mononuclear cells of BPD neonates. The inflammation-related pathway was highly enriched in the up-regulated genes. Ultimately, phospholipase C beta 1 (PLCB1), nidogen 1 (NID1), serum response factor binding protein 1 (SRFBP1), centrosomal protein 72 (CEP72), excision repair cross complementation group 6 like (ERCC6L), and peptidylprolyl isomerase like 1 (PPIL1) were identified as the main regulatory genes. The prediction model's calculation formula for risk score was PLCB1×0.26+NID1×0.97+SRFBP1×1.58+CEP72×(-0.36)+ERCC6L×2.14+PPIL1×0.67. The AUCs in the GSE32472 test dataset, GSE125873 dataset, and GSE220135 dataset were 0.88, 0.86, and 0.89, respectively. This prediction model could distinguish between non-BPD and BPD neonates. In conclusion, the prediction model based on inflammation-related pathway genes has a certain diagnostic value for BPD.

Multi-index comprehensive evaluation of the efficacy and response mechanism of immunotherapy in non-small cell lung cancer.

This research conducted multi-index comprehensive evaluations of the immunotherapeutic efficacy and response in non-small cell lung cancer (NSCLC). Forty-five patients with epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) wild-type advanced NSCLC who received immunotherapy were included. Immunohistochemistry was adopted to detect the expression levels of programmed death ligand 1 (PD-L1) with X-ray cross-complementing protein 1 (XRCC1) and excision repair cross-complementing group 1 (ERCC1) proteins in tumor tissues. Flow cytometry was utilized to measure the levels of T-cell subsets in peripheral blood before and after treatment. PCR-RELP method was employed to evaluate XRCC1 and ERCC1 gene polymorphisms in peripheral blood. According to the treatment effect, patients evaluated as complete response (CR), partial response (PR), and stable disease (SD) were categorized into the immune response group, and patients evaluated as progressive disease (PD) were categorized into the immune unresponsive group. The correlation between PD-L1 protein expression, XRCC1 and ERCC1 protein expression, gene polymorphisms, T-cell subpopulation levels, and treatment efficacy was analyzed. The therapeutic efficacy of patients with positive PD-L1 expression was better than that of patients with negative PD-L1 expression (P < 0.05). After treatment, peripheral blood CD3+ and CD4+ cell levels and Thl/Th2 cell levels were higher and CD8+ T cells were lower in the immune response group than in the immune unresponsive group (P < 0.05). Among the patients in the immune response group, peripheral blood CD3+ and CD4+ cell levels were higher and CD8+ T cells were lower in patients with positive PD-L1 expression than in patients with negative PD-L1 expression (P < 0.05). In the XRCC1 gene, the proportion of patients in the immune response group carrying the Arg/Trp + Trp/Trp genotype was higher than that of patients in the immune unresponsive group (P < 0.05). In the ERCC1 gene, the proportion of patients in the immune response group carrying the C/T + T/T genotype was higher than that of patients in the immune unresponsive group (P < 0.05). The positive expression rates of XRCC1 and ERCC1 in patients in the immune unresponsive group were higher than those in the immune response group (P < 0.05). PD-L1 protein expression, XRCC1 and ERCC1 protein expression, and gene polymorphisms are associated with immunotherapy outcome in EGFR/ALK wild-type advanced NSCLC patients, and may be biological indicators for predicting immunotherapy outcome in EGFR/ALK wild-type advanced NSCLC patients.

Lung cancer, predictive factor and ERCC1

Introduction: Excision repair cross-complementing group 1 (ERCC1) counteracts the cytotoxic effect of cisplatin through its role in DNA repair, and its expression level is a crucial factor for sensitivity to this drug. The objective of this study was to assess the impact of ERCC1 on tumor response and survival in patients with advanced non-small cell lung cancer (NSCLC) treated with a platinum-based regimen. Methods: Analysis of survival and tumor response based on the expression level of ERCC1 (detected by immunohistochemistry) in a cohort of NSCLC patients followed in a standard care setting. Results: Among the 77 cases of NSCLC included, ERCC1 expression was low in 64.9% of cases and high in 35.1% of cases. In the 52 patients treated with cisplatin, survival and tumor response were better in the low-expression group compared to the high-expression group: 14.35 months versus 9.49 months, p=0.022; Objective Response: 42.4% versus 0%, p=0.001. No significant difference was found based on protein expression level in patients treated with carboplatin. Conclusion: ERCC1 overexpression in patients treated with cisplatin predicts a poor tumor response and shorter survival.

Predictive and prognostic value of excision repair cross-complementing group 1 in patients with advanced gastric cancer

BackgroundTo define the optimal chemotherapy regimen for each patient we therefore used tissue from patients to identify molecular prognostic or predictive biomarkers.MethodsEndoscopic biopsy specimens from primary lesions and surgical specimens on a phase III trial in patients with unresectable advanced or recurrent gastric cancer treated with docetaxel with cisplatin plus S-1 (DCS) or cisplatin plus S-1 (CS), were collected. We measured the mRNA expression of ERCC1 and analyzed SNPs in GSTP1 and ERCC1.ResultsLow ERCC1 expression was associated with favorable prognosis for overall survival, OS by multivariable analysis (P = 0.001). There were significant interactions between the two treatment arms of DCS and CS, and ERCC1 mRNA expression. In patients with low ERCC1 expression of a favorable prognosis, DCS therapy was inferior to CS (P = 0.046). In addition to GSTP1 rs1695 (HR 1.728), ERCC1 rs3212980, ERCC1 rs2298881, ERCC1 rs3212964 with high expression of ERCC1 mRNA were associated with significantly worse prognosis with regard to OS.ConclusionsERCC1 mRNA is an independent prognostic factor and predictive marker that can be used to guide the addition of docetaxel. The SNPs of ERCC1 and GSTP1 could be also prognostic or predictive factors.

XPA tumor variant leads to defects in NER that sensitize cells to cisplatin.

Nucleotide excision repair (NER) reduces efficacy of treatment with platinum (Pt)-based chemotherapy by removing Pt lesions from DNA. Previous study has identified that missense mutation or loss of the NER genes Excision Repair Cross Complementation Group 1 and 2 (ERCC1 and ERCC2) leads to improved patient outcomes after treatment with Pt-based chemotherapies. Although most NER gene alterations found in patient tumors are missense mutations, the impact of mutations in the remaining nearly 20 NER genes is unknown. Towards this goal, we previously developed a machine learning strategy to predict genetic variants in an essential NER protein, Xeroderma Pigmentosum Complementation Group A (XPA), that disrupt repair. In this study, we report in-depth analyses of a subset of the predicted variants, including in vitro analyses of purified recombinant protein and cell-based assays to test Pt agent sensitivity in cells and determine mechanisms of NER dysfunction. The most NER deficient variant Y148D had reduced protein stability, weaker DNA binding, disrupted recruitment to damage, and degradation. Our findings demonstrate that tumor mutations in XPA impact cell survival after cisplatin treatment and provide valuable mechanistic insights to improve variant effect prediction. Broadly, these findings suggest XPA tumor variants should be considered when predicting chemotherapy response.

Prognostic Significance of Excision Repair Cross-Complementation Group 1 on Circulating Tumor Cells for Nasopharyngeal Carcinoma.

Liquid biopsy, including the detection of circulating tumor cells (CTCs), has emerged as a promising tool for cancer diagnosis and monitoring. However, the prognostic value of CTCs in nasopharyngeal carcinoma (NPC) remains unclear due to the lack of phenotypic characterization. The expression of Excision Repair Cross-Complementation Group 1 (ERCC1) and CTCs epithelial-mesenchymal transition (EMT) have been associated with treatment efficacy. In this study, we aimed to evaluate the prognostic significance of ERCC1 expression on CTCs and their EMT subtypes before treatment in NPC. We retrospectively analyzed 108 newly diagnosed locally advanced NPC patients who underwent CanPatrol™ CTC testing between November 2018 and November 2021. CTCs were counted and classified into epithelial, epithelial-mesenchymal hybrid, and mesenchymal subtypes. ERCC1 expression was divided into negative and positive groups. Clinical features and survival outcomes were analyzed. The positive rate of CTCs was 92.6% (100/108), with an ERCC1 positivity rate of 74% (74/100). Further analysis of the subtypes showed that positive ERCC1 on mesenchymal CTCs was associated with a later N stage (P = .01). Positive ERCC1 expression was associated with poor overall survival (OS; P = .039) and disease-free survival (DFS; P = .035). Further analysis of subtypes showed that the positive ERCC1 on mesenchymal-type CTCs was associated with poor OS (P = .012) and metastasis-free survival (MFS; P = .001). Our findings suggest that ERCC1 expression on CTCs may serve as a new prognostic marker for NPC patients. Evaluating CTCs subtypes may become an auxiliary tool for personalized and precise treatment.

CircMAP3K4 Suppresses H2O2-Induced Human Lens Epithelial Cell Injury by miR-630/ERCC6 Axis in Age-Related Cataract

Background Dysregulated circular RNAs (circRNAs) is involved in the pathogenesis of age-related cataract (ARC). Here, this study aimed to explore the function and mechanism of circMAP3K4 in ARC. Methods Human lens epithelial cells were exposed to hydrogen peroxide (H2O2) for functional experiments. qRT-PCR and western blotting analyses were used for the expression detection of genes and proteins. Cell proliferation was tested using cell counting kit-8 and EdU. Flow cytometry was applied to analyze cell apoptosis and cell cycle. The oxidative stress was evaluated by detecting the production of malondialdehyde (MDA), reactive oxygen species (ROS), and superoxide dismutase (SOD). The target relationship between miR-630 and circMAP3K4 or Excision repair cross-complementing group 6 (ERCC6) was analyzed by dual-luciferase reporter assay and RIP assay. Results CircMAP3K4 was lowly expressed in ARC patients and H2O2-induced HLECs. Functionally, forced expression of circMAP3K4 protected HLECs against H2O2-evoked proliferation inhibition, cell cycle arrest and the promotion of cell apoptosis and oxidative stress. Mechanistically, circMAP3K4 acted as a sponge for miR-630 to regulate the expression of its target ERCC6. MiR-630 was highly expressed while ERCC6 was lowly expressed in ARC patients and H2O2-induced HLECs. Up-regulation of miR-630 could reverse the protective effects of circMAP3K4 on HLECs under H2O2 treatment. In addition, inhibition of miR-630 suppressed H2O2-induced HLEC injury, which was abolished by ERCC6 silencing. Conclusion Forced expression of circMAP3K4 protected HLECs against H2O2-evoked apoptotic and oxidative injury via miR-630/ERCC6 axis, suggesting that circMAP3K4 may function as a potential therapeutic target for ARC.

Role of rs873601 Polymorphisms in Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

Lung cancer is still the most lethal malignancy in the world, according to the report of Cancer Statistics in 2021. Platinum-based chemotherapy combined with immunotherapy is the first-line treatment in lung cancer patients. However, the 5-year survival rate is always affected by the adverse reactions and drug resistance caused by platinum-based chemotherapy. DNA damage and repair system is one of the important mechanisms that can affect the response to chemotherapy and clinical outcomes in lung cancer patients. The objective of this study is to find the relationship between the polymorphisms of DNA repair genes with the prognosis of platinum-based chemotherapy in lung cancer patients. We performed genotyping in 17 single nucleotide polymorphisms (SNPs) of Excision Repair Cross-Complementation group (ERCC) genes and X-ray Repair Cross-Complementing (XRCC) genes of 345 lung cancer patients via Sequenom MassARRAY. We used Cox proportional hazard models, state, and plink to analyze the associations between SNPs and the prognosis of lung cancer patients. We found that the ERCC5 rs873601 was associated with the overall survival time in lung cancer patients treated with platinum-based chemotherapy (p = 0.031). There were some polymorphisms that were related to the prognosis in specific subgroups of lung cancer. Rs873601 showed a great influence on the prognosis of patients more than 55 years, Small Cell Lung Cancer (SCLC), and smoking patients. Rs2444933 was associated with prognosis in age less than 55 years, SCLC, metastasis, and stage III/IV/ED patients. Rs3740051 played an important role in the prognosis of SCLC and metastasis patients. Rs1869641 was involved in the prognosis of SCLC patients. Rs1051685 was related to the prognosis in non-metastasis patients. The ERCC5 rs873601 (G>A) was a valuable biomarker for predicting the prognosis in lung cancer patients treated with platinum-based chemotherapy.

BRCA1 expression and its combined low expression with PARP1 and ERCC1 predict chemotherapeutic response in ovarian cancer

Objective: This study aimed to evaluate the associations of immunohistochemical expressions of various deoxyribonucleic acid repair proteins, either individually or combined, with the response to platinum-based chemotherapy and overall survival in epithelial ovarian cancer.Material and Methods: This retrospective cohort study included patients with epithelial ovarian cancer who were treated by primary cytoreductive surgery with adjuvant platinum-based chemotherapy at Songklanagarind Hospital between January 2008 and December 2019. Immunohistochemistry analysis of breast cancer type 1 (BRCA1), poly (ADP-ribose) polymerase 1 (PARP1), X-ray repair cross-complementing 1 (XRCC1), and excision repair cross-complementation group 1 (ERCC1) expression was performed. Logistic regression was used to evaluate factors associated with chemotherapeutic response and Cox regression was applied for survival analysis.Results: Chemotherapeutic response was achieved in 205 of 249 patients (82.3%). Low BRCA1 expression was associated with good response (odds ratio [OR] 5.01, 95% confidence interval [CI] 1.78–14.1) and favorable overall survival (hazard ratio 0.61, 95% CI 0.38–0.98). PARP1, XRCC1, and ERCC1 showed no significant predictive or prognostic roles; however, combined low expression of PARP1/BRCA1 (OR 7.62, 95% CI 1.69–34.31) and ERCC1/BRCA1 (OR 6.98, 95% CI 1.5–32.52) additively enhanced response compared to high/high expressions.Conclusion: This study provides evidence that epithelial ovarian cancer (EOC) with low BRCA1 expression is more likely to be responsive to platinum-based therapy and is associated with favorable overall survival compared to tumors with high BRCA1 expression. The study supports a potential therapeutic strategy involving co-depletion of PARP1/BRCA and ERCC1/BRCA1 expression, although additional studies are needed.

Polymorphisms in ERCC1, ERCC4 and ERCC5 genes as biomarkers of susceptibility for pesticide-induced DNA damage in North-West Indian agricultural workers

BackgroundOccupational pesticides exposure has raised health concerns due to genotoxicity and accumulation of DNA damage. Polymorphisms in genes encoding enzymes involved in nucleotide excision repair (NER) may affect the individual’s susceptibility to pesticide toxicity.MethodsThis study evaluates the association of excision repair cross complementation group 1 (ERCC1) (8092 C > A, 3’UTR, rs3212986) and ERCC1 (19007 C > T, Asn118Asn, rs11615), ERCC4 (1244 G > A, Arg415Gln, rs1800067) and ERCC5 (3507 G > C, Asp1104His, rs17655) polymorphisms with pesticide-induced DNA damage in North-West Indian agricultural workers. The study population comprised 225 agricultural workers exposed to pesticides and 225 non-exposed controls.ResultsOur study demonstrate that exposed workers carrying variant ERCC1 8092AA genotype showed higher total comet DNA migration (p = 0.015) as well as increased frequency of cells showing DNA migration (p = 0.027). Exposed agricultural workers with variant ERCC4 1244AA (415Gln/Gln) and ERCC5 3507CC (1104His/His) genotypes exhibited elevation in total comet DNA migration (p < 0.01). However, genotypes of ERCC1 19007 C > T (Asn118Asn) showed no association with total comet DNA migration (p = 0.963), frequency of cells showing DNA migration (p = 0.423) as well as mean tail length (p = 0.432).ConclusionERCC1, ERCC4 and ERCC5 polymorphisms influence DNA damage and can be used as biomarkers of susceptibility for pesticide-induced DNA damage in North-West Indian agricultural workers.

Mechanism of Astragali Radix-Curcumae Rhizoma in treating gastric cancer based on network pharmacology and experimental verification

This study aims to investigate the mechanism of Astragali Radix-Curcumae Rhizoma(HQEZ) in the treatment of gastric cancer based on network pharmacology. Further, the SGC7901 cell model of gastric cancer was employed to validate the efficacy and key targets of the herb pair. Firstly, the CCK-8 assay was employed to evaluate the direct effect of HQEZ on the proliferation of gastric cancer SGC7901 cells. Then, network pharmacology methods were employed to investigate the active ingredients, key targets, and key signaling pathways involved in the treatment of gastric cancer with HQEZ. The results showed that HQEZ contained 18 potential active ingredients, such as quercetin, naringenin, and curcumin. The results of gene ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment suggested that the main targets of HQEZ in treating gastric cancer were involved in the regulation of protein serine/threonine kinase activity, activation of mitogen-activated protein kinase(MAPK) activity, cysteine-type endopeptidase activity, and negative regulation of protein serine/threonine kinase activity. The hypoxia-inducible factor-1(HIF-1) signaling pathway, ATP-binding cassette(ABC) transporters, cytochrome P450-mediated metabolism of xenobiotics, p53 signaling pathway, and cell apoptosis were key signaling pathways of HQEZ in treating gastric cancer. The cell experiments demonstrated that HQEZ significantly downregulated the expression of ATP-binding cassette subfamily B member 1(ABCB1), epidermal growth factor receptor(EGFR), phosphorylated serine/threonine kinase(p-AKT), hypoxia inducible factor 1 subunit alpha(HIF1A), B-cell lymphoma 2(BCL2), breast cancer susceptibility protein 1(BRCA1), DNA polymerase theta(POLH), ribonucleotide reductase M1(RRM1), and excision repair cross-complementation group 1(ERCC1), and upregulated the expression of tumor protein P53(TP53) and cysteinyl aspartate-specific proteinase(CAPS3). Finally, a multivariate COX regression model was adopted to study the relationship between gene expression and clinical information data of gastric cancer patients in the TCGA database, which demonstrated that the key targets of HQEZ were associated with the poor prognosis in gastric cancer patients. Further feature selection using the LASSO algorithm showed that EGFR, HIF1A, TP53, POLH, RRM1, and ERCC1 were closely associated with the survival of gastric can-cer patients. In conclusion, HQEZ regulates the expression of genes involved in DNA repair, survival, and apoptosis in gastric cancer cells via multiple targets and pathways, assisting the treatment of gastric cancer.

The Relationship between Single Nucleotide Polymorphism of ERCC1 Gene and the Response to Platinum Based Chemotherapy in Egyptian Non-Small Cell Lung Cancer Patients

Abstract Background Lung cancer (LC) is the second most common cancer diagnosed in both males and females. There are two subtypes of LC. Non-small cell lung cancer (NSCLC) is the major one. Treatment options for NSCLC depends mainly on the stage at diagnosis. The majority of the patients are diagnosed at advanced stages at time of presentation. Therefore, chemotherapy and radiotherapy play the dominant role in treatment of advanced NSCLC. The most commonly used chemotherapy is platinum-based chemotherapy as cisplatin and carboplatin and third generation drugs as vinorelbine and gemcitabine. The efficacy of platinum-based chemotherapy is limited by chemoresistance. The excision repair cross complementation group 1(ERCC1) gene is a member of nucleotide excision repair pathway that plays a critical role in the DNA repair by removing DNA covalent helix-distorting adducts. Aim of the Work In this study investigated the relationship between single nucleotide polymorphism of ERCC1 rs11615 and the response to platinum-based chemotherapy in Egyptian NSCLC patients in order to prevent the non-necessary exposure to the toxic effect of chemotherapy. Patients and Methods This is a cross-sectional study conducted on 50 NSCLC patients who were recruited from the Oncology Clinic in Ain Shams University Hospitals; twenty of them were responders to platinumbased chemotherapy and the other 30 were non-responders according to RECIST criteria. All subjects underwent full medical history focusing on tobacco smoking and family history of cancers, thorough clinical examination, histological diagnosis of NSCLC and TNM classification, radiological studies: computed tomography of chest and abdomen and laboratory investigations in the form of: complete blood picture (CBC), liver function tests and kidney function tests. Detection of the ERCC1 (T/C) polymorphism by realtime PCR was done for both the responders' and the non-responders' groups. Results There was no significant statistical difference observed between the responders’ and nonresponders’ groups regarding the genotype frequencies nor the allelic frequency (p &amp;gt; 0.05). Conclusion The present study did not confirm the presence of significant association between the genotypic frequencies nor the allelic frequencies of the ERCC1 rs 11615 among the responders' and the non-responders' groups. Further studies with higher sample size are needed to clarify the association.

Association of Chemotherapy Response Score with Multidrug Resistance 1 and CA125 ELIMination Rate Constant K in Patients with Advanced Ovarian Cancer Treated with Neoadjuvant Chemotherapy.

The relationship between chemotherapy response score (CRS), a widely used response predictor of neoadjuvant chemotherapy-interval debulking surgery (NAC-IDS), and multidrug resistance 1 (MDR1) and CA125 ELIMination rate constant K (KELIM), is undetermined. We evaluated CRS in advanced ovarian cancer patients undergoing NAC and looked for associations between CRS and MDR1 and CA125 KELIM. Our aim was to predict the therapeutic effect of NAC before interval debulking surgery (IDS) by examining its association with CRS. This retrospective cohort study included patients who underwent NAC-IDS (first-line treatment) at Kurume University Hospital, Japan, between 2004 and 2017. CRS association with MDR1 and CA125 KELIM was examined using Cox proportional hazard regression analyses. Survival curves used Kaplan-Meier method, and survival differences between groups used log-rank test. Overall, 55 patients were classified into CRS1 (n=22), CRS2 (n=19), and CRS3 (n=14). The CRS3 group had a significantly better prognosis than the CRS1 or CRS2 group. CRS, age, and IDS status were clinical prognostic factors for ovarian cancer. MDR1 positivity for excision repair cross-complementing group 1, β-tubulin, and Y-box binding protein-1 occurred in 15, 17, and 11 patients, respectively, but these were not associated with CRS. CA125 KELIM was <0.5 (n=8), 0.5-1.0 (n=30), and ≥ 1.0 (n=17) but not associated with CRS. CRS is reconfirmed as a treatment response predictor for NAC-IDS, but its association with drug resistance factors remains unconfirmed.

Effect of ERCC1 polymorphisms on the response to platinum-based chemotherapy: A systematic review and meta-analysis based on Asian population.

Platinum-based chemotherapy is one of the most common treatments for many cancers; however, the effect of chemotherapy varies from individual to individual. Excision repair cross complementation group 1 (ERCC1) is widely recognized as a key gene regulating nucleotide excision repair (NER) and is closely associated with platinum response. Many studies have yielded conflicting results regarding whether ERCC1 polymorphisms can affect the response to platinum and overall survival (OS). Therefore, it is necessary to perform a meta-analysis of patients with specific races and cancer types. Eight databases (EMBASE, PubMed, Cochrane Library, Chinese National Knowledge Infrastructure, Scopus, VIP, China Biology Medicine disc and Wanfang databases) were searched. Results were expressed in terms of odds ratios (ORs), hazard ratios (HRs) and 95% CIs. In this study, rs11615, rs2298881 and rs3212986 SNPs were studied. In the comparison between CT and TT on the response to platinum, esophageal cancer [I2 = 0%, OR = 6.18, 95% CI(1.89,20.23), P = 0.003] and ovarian cancer [I2 = 0%, OR = 4.94, 95% CI(2.21,11.04), P<0.001] showed that the rs11615 CT genotype predicted a better response. In the comparison between CC and TT, ovarian cancer [I2 = 48.0%, OR = 6.15, 95% CI (2.56,14.29), P<0.001] indicated that the CC genotype predicted a better response. In the meta-analysis of OS, the CC genotype was related to longer OS than TT in ovarian cancer [TT vs CC: I2 = 57.7%, HR = 1.71, 95% CI (1.18, 2.49), P<0.001]. The ERCC1 rs11615 polymorphism was related to the response to platinum and OS, but the correlation is based on specific cancer types in the Asian population.

The XRCC1 and TP53 gene polymorphisms are associated with advanced-stage disease and early distant metastasis at diagnosis in non-small cell lung cancer.

Studies on single nucleotide polymorphisms (SNPs) in non-small cell lung cancer (NSCLC) suggest that DNA repair capacity may have prognostic implications for disease recurrence and survival. However, there is no study investigating the relationship between SNPs and the risk of metastasis at the time of initial diagnosis in patients with NSCLC. This study aimed to investigate the potential predictive value of SNPs in detecting the risk of metastasis at the time of initial diagnosis and poor prognosis in patients with NSCLC. In this prospective cohort study, we evaluated 275 patients with NSCLC. Analysis of SNPs from peripheral blood cells was performed by a polymerase chain reaction. Excision repair cross-complementing group 1 (ERCC1)- Asn118Asn, excision repair cross-complementing group 2 (ERCC2)-Lys751Gln, X-ray repair cross-complementing group 1 (XRCC1)-Arg399Gln, and tumor protein 53 (TP53)-Arg72Pro polymorphisms were evaluated in conjunction with the development of metastasis. The ERCC1 normal genotype, ERCC2 heterozygote genotype, XRCC1 normal genotype, and TP53 normal genotype were associated with a higher stage and more advanced-stage disease at the time of initial diagnosis (P = 0.027, 0.005, <0.001, and 0.006, respectively). Also, XRCC1 normal genotype and TP53 normal genotype were associated with the risk of metastasis at the time of initial diagnosis (P = <0.001 and 0.002, respectively). Moreover, the XRCC1 normal genotype was associated with the risk of brain metastasis at the time of initial diagnosis (P = 0.031). We showed that SNPs are related to a higher stage and more advanced-stage disease at the time of initial diagnosis in patients with NSCLC, and XRCC1 and TP53 gene polymorphisms are associated with the risk of metastasis. These results may contribute to the identification of high-risk groups and may help to earlier diagnosis and treatment in patients with NSCLC.